Triazino(4,3-D) (1,4) benzodiazepine-3,4,7-triones

ABSTRACT

Compounds having the structure   WHEREIN R1 is hydrogen, alkyl, phenyl, or phenylmethyl; R2 is hydrogen or alkyl; R3 is alkyl or arylalkyl; and R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, aldoxy, or alkylthio have anti-inflammatory activity.

United States Patent 11 1 Wade et al.

[ Aug. 5, 1975 TRIAZINO( 4,3-D) (1,4) BENZODIAZEPINE-3,4,7-TRIONES Inventors: Peter C. Wade, Pennington. N.J.; B.

Richard Vogt, Yardley, Pa.

Assignee: E. R. Squibb 84 Sons, Inc., Princeton, NJ.

Filed: Aug. 9, 1974 Appl. No.: 495,970

US. Cl. 260/2393 T; 424/249 Int. Cl. .4 C07d 471/04 Field of Search 260/2393 T Primary E.ruminer-Henry R. .liles Assistant E.\'aminerRobert T. Bond Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Donald J. Barrack ABSTRACT Compounds having the structure wherein R, is hydrogen, alkyl, phenyl, or phenylmethyl; R is hydrogen or alkyl; R; is alkyl or arylalkyl; and R, is hydrogen, halogen, nitro, cyano. trifluoromethyl. alkyl, aldoxy. or alkylthio have antiinflammatory activity.

6 Claims, N0 Drawings TRIAZlNO(4.3-D) (1,4) BENZODIAZEPINE-3.4.7-TRIONES SUMMARY OF THE INVENTION Compounds having the structure are anti-inflammatory agents.

In formula I, and throughout the specification, the symbols are as defined below:

R can be hydrogen, alkyl, phenyl, or phenylmethyl;

R, can be hydrogen or alkyl;

R can be alkyl or arylalkyl; and

R can be hydrogen, halogen (preferably fluorine,

chlorine or bromine), nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio.

The term alkyl" as used throughout the specification, either by itself or as part of a larger group, refers to both straight and branched chain alkyl groups containing one, two, three, or four carbon atoms.

The term alkoxy as used throughout the specification, refers to compounds of the formula YO wherein Y is alkyl as defined above.

The term halogen as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.

The term arylalkyl as used throughout the specification refers to an alkyl group substituted with phenyl or phenyl having one or two substituents selected from alkyl, alkoxy and halogen.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention are produced from compounds having the formula wherein R; can be halogen (preferably bromine or chlorine), sulfliydryl, alkoxy, alkylthio, or phenylalkylthio and R.; can be alkyl, phenyl, or phenylmethyl. The compounds of formula II are known; see, for example, US. Pat. No. 3,414,563 and Swiss Pat. No. 485,742.

Reaction of a benzodiazepine of formula II with 4- morpholineglyoxylic acid, hydrazide yields a compound having the structure III The reaction can be run in a non-reactive polar solvent, e.g., dimethylformamide, n-butanol, etc. at a temperature of about 50C to 200C, for about 5 minutes to 24 hours, preferably at from 60C to C for 10 minutes to 3 hours. The benzodiazepine of formula II and 4- morpholineglyoxylic acid, hydrazide are reacted in approximately a 1:1 molar ratio.

Alternatively, compounds of formula II] can be prepared by first reacting a benzodiazepine of formula II with a carbazate having the formula wherein Z is t-butyl, phenylmethyl, or phenylmethyl substituted with one or more alkoxy or nitro groups, to yield an intermediate having the structure l-IN-N-C-OZ H II Reaction of a compound of formula IV with an ester of oxalic acid and analkanol (preferably a lower alcohol having one, two, or three carbons) and an anhydrous acid (preferably oxalic acid) yields the corresponding compound of formula III. The reaction can be run without a solvent or in a non-reacting organic solvent at a temperature of from about 50C to 250C for about 5 minutes to 24 hours, preferably from about 60C to 150C for about 30 minutes to 6 hours. The benzodiazepine of formula II, the oxalic acid ester, and the strong acid are used in approximately a l:l:l molar ratio.

In order to obtain the triazinobenzodiazepines of formula l, a tn'azinobenzodiazepine of formula III is reacted with an appropriate base, e.g., thallous ethoxide, in approximately a 1:1 molar ratio, to obtain a salt having the structure The salt of formula V is subsequently reacted with a compound having the formula R X wherein X can be chlorine, bromine, iodine, alkylsulfonate (e.g., methanesulfonate) or arylsulfonate (e.g., toluenesulfonate), to obtain a compound having the structure 1 VI M 4451 N 'o l R The reaction of a triazinobenzodiazepine of formula III with thallous ethoxide is run in a non-reactive polar solvent, e.g., dimethylformamide at a temperature of from C to 180C, preferably room temperature, for a period of about 1 minute to 5 hours, preferably for minutes to 1 hour. The reaction of a salt of formula V with a compound of the structure R -X is run at about 50C to 200C for a period of about minutes to 48 hours, preferably at 80C to 140C for 2 to 24 hours.

Reduction of triazinobenzodiazepines of formula VI, wherein R is benzyl, to yield compounds having the structure F I O VII the l l-position are particularly preferred. Compounds of formula I wherein R,.is halogen are preferred, chlorine being the most preferred.

The triazinobenzodiazepines of formula I are useful in treating inflammation in mammalian species, e.g., rats, dogs, cats, monkeys, etc. Joint tenderness and stiffness (in conditions such as rheumatoid arthritis) are relieved by the above described compounds.

The compounds of this invention are formulated for use as anti-inflammatory agents according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs, or powders, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. The compounds of this invention may be administered in amounts of 100 mg/kg/day to 2 g/70kg/day, perferably 100 mg/70kg/day to l g/70kg/day.

The following examples are specific embodiments of this invention.

EXAMPLE 1- l l-Chloro-2,8dihydro-8-methyl-2-(phenylmethyl)-astriazino[4,3-d][ 1,4 ]benzodiazepine-3,4,7( 6E )-trione A. 1 l-Chloro-2,8-dihydro-8-methyl-as-tria2inol4,3-d]- l ,4]benzodiazepine-3,4,7( 6I;I )-trione 5,7-Diehloro- 1 -methyl- 1 ,4-benzodiazepinone-2 (20 grams, 0.08 moles) and 4-morpholineglyoxylic acid, hydrazide (15 grams, 0.088 mole) are mixed together in 300 milliliters of dimethylformamide for 30 minutes while heating at 100C. The solvent is stripped off and 400 milliliters of absolute ethanol is added to the residue. A precipitate forms and the mixture is stirred overnight. The precipitate is filtered off and stirred in 200 milliliters of water for 2 hours at room temperature. The solid material is filtered off and digested for 1 hour as a slurry in 2 liters of absolute ethanol. While still hot, the mixture is filtered and l l-chloro-2,8- dihydro-8-methyl-as-triazino[4,3-d][ 1,4]benzodiazepine-3,4,7(6I;I)-trione (the filter cake) is dried under vacuum at 120C for 4 hours. The product has an indistinct melting point; partial melting and decomposition occur from 342C to 365C, where complete melting and decomposition occur.

B. l 1 Chloro-2,8-dihydro-8-methyl-2-(phenylmethyl )-astriazino[4,3-d][ l ,4]benzodiazepine-3,4,7(6I;I)-trione l l-Chloro-2,8-dihydro-8-methyl-as-triazino[ 4,3 d][1,4]benzodiazepine-3,4,7(6I;I)-trione (2.93 grams, 0.01 mole) is dissolved in 50 milliliters of warm (ca. 70C) dimethylformamide and treated with thallous ethoxide (2.04 grams, 0.01 mole). After stirring at 25C for 2 hours, the solution is diluted with ml of ether and the resulting precipitate filtered off. The precipitate is dried at 25C for 2 hours and then suspended in milliliters of refluxing toluene and treated with benzyl bromide (4 grams, 0.022 mole). Refluxing is continued for 3 hours. The hot reaction mixture is filtered through infusorial earth and the filtrate is stripped of solvent. The residue is taken up in chloroform and washed through a 5 X 10 cm. column of magnesium silicate with 1 liter of chloroformzcthyl acetate (6:4). The solvents are stripped off and the residue recrystallized from ethanol: chloroform (5:1 to give 2.2 grams of the title compound. melting point 24l243C.

EXAMPLE 2 1 1-Ch1oro-2,8-dihydro-2,8-dimethy1-as-triazino [4,3-d][ 1 ,4]benzodiazepine-3,4,7(61;l)-trione 1 1-Chloro-2,S-dihydro-8-methy1-as-triazino[4,3- d][1,4lbenzodiazepine-3,4,7(6l -1)-trione (3.54 grams, 0.012 mole, prepared as described in Example 1 is dissolved in milliliters of warm (ca 70C) dimethylformamide and treated with thallous ethoxide (2.46 grams, 0.012 mole). The solution is stirred at 25C for 2 hours and then diluted with 75 milliliters of ether; the resulting precipitate is filtered off. The precipitate is dried at 25C for 2 hours and then suspended in methyl with 2 liters of chloroform. The solvent is removed under vacuum and the residue stirred as a suspension in 100 milliliters of methanol for 1 hour. The insoluble material is filtered off and dried overnight at 80C to give 1.0 gram of the title compound, melting point 350-35 3C. An additional 1.5 grams of less pure material is recovered from the column.

EXAMPLES 3 1 1 Following the procedure of Example 1, but substituting the compounds indicated in column 1 below for 5,7- dichlorol -methy1-1 ,4-benzodiazepinone-2, the compounds indicated in column 11 are obtained.

Example Column 1 Column 11 methyl 1 ,4-benzodiazepinone-2 4 S-chloro-1-methyl-7-nitro-1,4-benzodiazepinone-Z 5 5-ch1oro-7-ethylthiol-methyl- 1 ,4-benzodiazepinone-Z 6 5-ch1oro-1 ,7-dimethyl- 1 ,4-benzodiazepinone-2 7 5-chlorol ,3-dimethy1-7-( trifluoromethyl 1 ,4-benzodiazepinone-2 8 8-bromo-5-ethoxy 1 -phenyl- 1 ,4-benzodia zepinone-Z 9 7-cyano-1-(phenylmethyl)-5-methylthio)- 1 4-benzodiazepinone-2 1O 1 phenylmethyl-7-chlorol .4-benzodiazepin 2-one-5-thione 5-ch1oro-1-pheny1-7-ethy1- 1 ,4-benzodiazepinone-2 1 ,4 ]benzodiazepine-3,4,7(61i)-trione 2,8-dihydro-8-methyl-l l-nitro-2-( phenylmethyl )-as-triazino[4,3d 1,4]benzodiazepine-3,4,7( 6fl)-trione 2 ,8-dihydro-8-methyl-1 l-( ethylthio)-2- (phenylmethyl )-as-triazino[4,3-d][ 1 ,4]- benzodiazepine-3.4 7( 6g )-trione 2,8-dihydro-8,1 1-dimethy1-2-( phenylmethyl )-as-triazino[4,3-d][ 1 ,4]benzodia zepine-3 ,4,7( 6l -l )-trione 2,8-dihydro-6,8-dimethy1-2-( phenylmethyl 1 1-( trifluoromethyl )-as-triazino[ 4,3-d

[ 1 ,4]benzodiazepine-3,4,7( oflytrione 1 0-bromo-2,8-dihydro-8-phenyl-2-( phenylmethyl )-as-triazino[4,3-d 1,4]benzodia zepine-3,4,7( 6g )-trione 1 1-cyano-2,8-dihydro-2,8- [di-( phenylmethyl as-triazino[4.3-d][ 1,4]benzodiazepine- 3,4,7(61;1)-trione 1 1-chloro-2,8-dihydro-2,8-[di-(phenyl methyl ]-as-triazino[ 4,3-d][ 1 ,4 benzodiazepine-3 ,4,7( 6l l )-trione S-phenyl-l l-ethyl-2 ,8-dihydro-2-( phenylmethyl )-as-triazino[4,3-d][ 1 ,4 ]benzodiazepine-3 ,4,7(6L1)-trione iodide milliliters) and refluxed for 6 hours. The methyl iodide is allowed to evaporate and the residue extracted in a Soxhlet with chloroform. The resulting chloroform solution (ca. 400 milliliters) is washed through a column of grams of magnesium silicate EXAMPLES 12 20 Following the procedure of Example 1, but substituting the compounds indicated in column 1 below for 45 benzyl bromide, the compounds indicated in column 11 are obtained.

Example Column 1 Column 11 12 4-bromo-1-phenylbutane 13 3-bromo-1-(2 ch1oropheny1)butane 14 2-bromo- 1 -pheny1butane 15 2-bromo- 1 3 ,4dichlorophenyl ethane 16 3-bromo- 1 2-methoxyphenyl )propane 17 2-bromo- 1-( 3,5-dimethylphenyl ethane 1 8 4-fluorophenylmethyl bromide 19 1 -bromo-2-methylpropane 20 Z-bromopropane EXAMPLE 21 l l-Chlore-2,8-dihydro-2-methyl-as-triazino[4,3 d][ 1 ,4]benzodiazepine-3,4.7( 6E )-trione A. l l-Chloro-2,8-dihydro-8-( phenylmethyl )-as-triazino [4,3-d][1,4]benzodiazepine-3,4,7(6l -l)-trione EXAMPLES 22 -2o Following the procedure of Example 21, but substituting the compound indicated in column I below for 5,7-dichloro-l-benzyl-1,4-benzodiazepinone-2 and the compound indicated in column ll below for methyl iodide, the compound indicated in column III below is obtained.

Example Column l Column ll Column Ill 22 -chloro-7-nitrol-benzyll ,4-benzodiazepinone-2 23 S-chloro-B-methoxyl benzyll ,4-benzodiazepinone-Z 24 5-chIoro-3 7-diethyll benzyll ,4-benzodiazepinone-2 25 5-chloro-7'ethylthiol-benzyl 1.4-benzodiazepinone-2 26 5-chloro-7-( trifluoromethyl l-benzyl l ,4-benzodiazepinone-2 B. l l-Chloro-2,8-dihydro-8-(phenylmethyl )-2methyl-astriazino[4,3-d][ l,4]benzodiazepine-3,4,7(6lj)-trione l 1-Chloro-2,8-dihydro-8-( phenylmethyl)-as-triazino [4,3-d][ l ,4]benzodiazepine-3,4,7(6|;l )-trione (0.02 mole) is suspended in 100 milliliters of tetrahydrofuran Thallous ethoxide (0.02 mole) is added to the suspension and stirred for 1 hour at room temperature to give the salt.

The salt is suspended in 200 millilters of refluxing toluene and treated with methyl iodide. Refluxing is continued for 3 hours followed by filtering of the hot solution, evaporation of the filtrate, washing of the residue and recrystallizing of l l-chloro-2,8-dihydro-8- (phenylmethyl)-2-methyl-as-triazino[4,3-d][ 1,4]benzodiazepine-3,4,7(6l;i)-trione.

C. l l-Chloro-2,8-dihydro-2-methyl-as-triazino[4,3-d]- l,4]benzodiazepine-3,4,7(6l;l)-trione l l-Chloro-2,8-dihydro-8-(phenylmethyl)-2-methylas-triazino[4,3-d][ l,4]benzodiazepine-3,4,7( 6L!)- trione (0.01 mole) is hydrogenated at 60C in 300 milliliters of acetic acid containing 0.3 g of pre-reduced Raney nickel. The initial hydrogen pressure is 60 psi. The reduction is stopped after 0.01 mole of hydrogen is absorbcd, the catalyst is filtered off, and the solvent is evaporated. The residue is stirred with water and l lchloro-Z,8-dihydro-2-methyl-as-triazino[4,3- d][l,4]benzodiazepine-3.4,7(6l;l)-trione is filtered off and dried.

3-bromol 3,4-dichlorophenyl )propane 2-bromopropane bromoethane 2-bromol-( 3-chlorophenyl )ethane 4-bromol-( 2-methoxyphenyl )butane What is claimed is: l. A compound having the formula wherein R is hydrogen, alkyl, phenyl or phenylmethyl; R is hydrogen or alkyl; R, is alkyl or arylalkyl; and R is hydrogen, halogen, nitro, cyano, trifluoromethyl, al kyl, alkoxy or alkylthio; wherein alkyl refers to alkyl groups having one to four carbon atoms, alkoxy refers to alkoxy groups having one to four carbon atoms, and arylalkyl refers to an alkyl group substituted with phenyl or phenyl having one or two alkyl, alkoxy or halogen substituents.

2. A compound in accordance with claim 1 wherein R is alkyl.

3. A compound in accordance with claim 1 wherein R is phenylalkyl.

4. A compound in accordance with claim 3 wherein R is phenylmethyl or phenylethyl.

5. The compound in accordance with claim 1 having the name I l-chloro-2,8-dihydro-8-methyl-2- (phenylmethyl)-as-triazino[4,3-d][ 1,4]benzodiazepine-3,4,7(6l;l)-trionc.

6. The compound in accordance with claim 1 having the name 1 l-chloro-2,8-dihydro-2,8-dimethyl-astriazino[4,3-d][ 1,4]benzodiazepine-3,4,7(6l;l)-trione.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,898,212 DATED gust 5 1975 INV ENTOR(S) 1 Peter C. Wade and B. Richard Vogt It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below:

Abstract page, second to last line, "aldoxy" should read -alkoxy.

Signed and Scaled this eleventh D Of November 19 75 [SEAL] A ttes t:

RUTH C. MASON C. MwRSHALL DANN (ummr'ssinncr of Parenrx um] Trademurkx Arresting Officer 

1. A COMPOUND HAVING THE FORMULA
 2. A compound in accordance with claim 1 wherein R3 is alkyl.
 3. A compound in accordance with claim 1 wherein R3 is phenylalkyl.
 4. A compound in accordance with claim 3 wherein R3 is phenylmethyl or phenylethyl.
 5. The compound in accordance with claim 1 having the name 11-chloro-2,8-dihydro-8-methyl-2-(phenylmethyl)-as-triazino(4,3 -d)(1,4)benzodiazepine-3,4,7(6H)-trione.
 6. The compound in accordance with claim 1 having the name 11-chloro-2,8-dihydro-2,8-dimethyl-as-triazino(4,3-d)(1, 4)benzodiazepine-3,4,7(6H)-trione. 